Success,failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache

Drug-resistant chronic cluster headache (CH) is an unremitting illness with excruciatingly severe headaches that occur several times daily. Starting in 2000, a total of 19 patients with long-lasting chronic CH, with multiple daily attacks unresponsive to all known prophylactics, received stimulation of the posterior inferior hypothalamic area ipsilateral to the pain as treatment. We report long-term follow-up (median 8.7 years, range 6–12 years) in 17 patients. Long-lasting improvement occurred in 70% (12 of 17): 6 are persistently almost pain-free; another 6 no longer experience daily attacks but rather episodic CH interspersed with long-lasting remissions. In 5 of 6 almost pain-free patients, the stimulators have been off for a median of 3 years (range 3–4 years). Five patients did not improve: 4 had bilateral CH, and 3 developed tolerance after experiencing relief for 1–2 years. Adverse events are electrode displacement (n = 2), infection (electrode n = 3; generator n = 1), electrode malpositioning (n = 1), transient nonsymptomatic third ventricle hemorrhage (n = 1), persistent slight muscle weakness on one side (n = 1), and seizure (n = 1). This exceptionally long follow-up shows that hypothalamic stimulation for intractable chronic CH produces long-lasting improvement in many patients. Previous experience was limited to a median of 16 months. Important new findings are as follows: stimulation is well tolerated for many years after implantation; after several years during which stimulation was necessary for relief, a persistent almost pain-free condition can be maintained when stimulation is off, suggesting that hypothalamic stimulation can change disease course; tolerance can occur after marked long-lasting improvement; and bilateral chronic CH seems to predict poor response to hypothalamic stimulation.     

Type I interferons as vaccine adjuvants against infectious diseases and cancer

Presently, new attention is given to type I interferons (IFNs) as essential factors linking innate and adaptive immunity. Several studies provided evidence about the importance of IFN-alpha in the differentiation of the Th1 subset, in the generation and activity of cytotoxic T lymphocytes, in the enhancement of a primary antibody response and in the activation of dendritic cells. Owing to their immunomodulatory properties, type I IFNs can represent good candidates to be used as adjuvants for vaccination. In the present review, we summarize recent studies in humans and in animal models, suggesting a possible application of type I IFNs as adjuvants for the development of more effective vaccines against infectious diseases and cancer.     

Vi-CRM 197 as a new conjugate vaccine against Salmonella Typhi

An efficacious, low cost vaccine against typhoid fever, especially for young children, would make a major impact on disease burden in developing countries. The virulence capsular polysaccharide of Salmonella Typhi (Vi) coupled to recombinant mutant Pseudomonas aeruginosa exoprotein A (Vi-rEPA) has been shown to be highly efficacious. We investigated the use of carrier proteins included in infant vaccines, standardized the conjugation process and developed key assays required for routine lot release at production scale. Vi from a BSL1 organism, Citrobacter freundii, strain WR7011, was used as an alternative to Vi from S. Typhi. We showed that Vi conjugated to CRM₁₉₇, a non-toxic mutant of diphtheria toxin, widely used in commercial vaccines, was produced at high yield. Vi-CRM₁₉₇ proved immunogenic in animal studies, even without adjuvant. Thus, Vi-CRM₁₉₇ appears to be a suitable candidate for the development of a commercially viable, effective typhoid vaccine for developing countries.     

Drug-resistant chronic migraine: the Italian GON project

Chronic daily headache is a major problem due to severe disability and high socio-economic costs. In the last years, some trials have shown potential benefit from new therapeutic approach by occipital neurostimulation techniques, already applied with some success for the treatment of chronic cluster headache. Due to the extremely heterogeneous population suffering from refractory chronic daily headaches, we propose a national multicenter experimental study involving Italian ANIRCEF Headache Centres with the aim to evaluate the efficacy of occipital neurostimulation in a selected group representative for the drug-resistant chronic migraine. Patients with chronic migraine according to Manzoni's modified IHS criteria-2011, with or without medication overuse headache, will be selected. Duration of illness should be at least 2 years and pharmacological refractoriness defined strictly for experimental-surgical purposes as those patients who have properly tried without success almost all available classes of prophylactic medications. Those presenting with medication overuse should have tried at least two previous detoxification treatments. A full psychopathological assessment will be performed by a psychiatrist, to exclude mainly psychotic disorder, ongoing severe status of an affective disorder, severe post traumatic stress disorder. Headache characteristics and abortive treatments used will be reported daily on a predisposed diary during 3-month baseline and continuously through the post implant follow up, while disability and QoL scale (MIDAS, SF-12) will be completed baseline, 6 and 12 months after implant.     

Melatonin down‐regulates MDM2 gene expression and enhances p53 acetylation in MCF‐7 cells

Compelling evidence demonstrated that melatonin increases p53 activity in cancer cells. p53 undergoes acetylation to be stabilized and activated for driving cells destined for apoptosis/growth inhibition. Over‐expression of p300 induces p53 acetylation, leading to cell growth arrest by increasing p21 expression. In turn, p53 activation is mainly regulated in the nucleus by MDM2. MDM2 also acts as E3 ubiquitin ligase, promoting the proteasome‐dependent p53 degradation. MDM2 entry into the nucleus is finely tuned by two different modulations: the ribosomal protein L11, acts by sequestering MDM2 in the cytosol, whereas the PI3K‐AkT‐dependent MDM2 phosphorylation is mandatory for MDM2 translocation across the nuclear membrane. In addition, MDM2‐dependent targeting of p53 is regulated in a nonlinear fashion by MDM2/MDMX interplay. Melatonin induces both cell growth inhibition and apoptosis in MCF7 breast cancer cells. We previously reported that this effect is associated with reduced MDM2 levels and increased p53 activity. Herein, we demonstrated that melatonin drastically down‐regulates MDM2 gene expression and inhibits MDM2 shuttling into the nucleus, given that melatonin increases L11 and inhibits Akt‐PI3K‐dependent MDM2 phosphorylation. Melatonin induces a 3‐fold increase in both MDMX and p300 levels, decreasing simultaneously Sirt1, a specific inhibitor of p300 activity. Consequently, melatonin‐treated cells display significantly higher values of both p53 and acetylated p53. Thus, a 15‐fold increase in p21 levels was observed in melatonin‐treated cancer cells. Our results provide evidence that melatonin enhances p53 acetylation by modulating the MDM2/MDMX/p300 pathway, disclosing new insights for understanding its anticancer effect.     

Geriatric Medicine in Italy in the Time of COVID-19

The journal of nutrition, health & aging -     

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) inflammatory network

HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP) is a systemic immune-mediated inflammatory disease and tissues other than nervous can be damaged, mainly ocular, rheumatic and dermatologic. Over 90% of HTLV-1-infected individuals remain lifelong asymptomatic and this retrovirus persists indefinitely in their CD4+ T-lymphocytes. The infection is maintained due to the proliferation of lymphocytes that harbor a provirus and express HTLV-1 proteins, particularly Tax, promoting an active and selective expansion of infected T cells. High proviral load is related to disease progression, which is correlated to disequilibrium between host and virus. Cytotoxic T lymphocytes are abundant and chronically activated in asymptomatic carriers and in HAM/TSP patients. The asymptomatic carriers were shown to have a high frequency of pro-inflammatory monocytes and anti-inflammatory IL-10+CD4+ and IL-10+CD8+ T-cells, as an immunoregulatory mechanism to counterbalance the monocyte-derived TNF-alpha. A putative immunomodulatory event would be the key to control their overall immunological status. In HAM/TSP, a pro-inflammatory microenvironment is the hallmark of the immunological profile. Enhanced frequency of activated CD8+ T-cells (HLA-DR+) in combination with high CD18 surface expression has been seen. In blood and cerebrospinal fluid, increased levels of Type-1 cytokines, as interferon-(IFN)-gamma, Tumor Necrosis Factor (TNF)-alpha, Interleukin (IL)-2, and pro-inflammatory IL-6, can be found. Concerning the progression, HLA polymorphisms may influence HAM/TSP and the allele HLA-A*2 has been associated with protection. The authors showed that HAM/TSP is strongly associated with a decreased percentage of B-cells, with enhanced T/B-cell ratio and activated CD8+ T-cells. These immunological parameters have been proposed as a prognostic biomarker for HAM/TSP.     

Chromosome radiosensitivity in human G2 lymphocytes and cell-cycle progression.

PURPOSE: To investigate the possibility that the differential G2-phase radiosensitivity of human peripheral blood lymphocytes, found in normal individuals using the 'G2-phase chromosome radiosensitivity assay', could be attributed to heterogeneity in cellular progression to mitosis rather than differences in radiosensitivity. MATERIALS AND METHODS: Human peripheral blood lymphocytes, from four different donors, were exposed to 50 cGy X-rays and sampled at different times. The progression of cells into mitosis was monitored by 5-bromo 2'-deoxyuridine (BrdUrd) incorporation. RESULTS: The heterogeneous G2-phase chromosome radiosensitivity among different donors was abolished when homogeneous G2-phase cell populations were scored; they contained similar frequencies of cells in early or late G2-phase. CONCLUSIONS: The heterogeneous G2-phase chromosome radiosensitivity, usually found in different normal donors, is caused by the analysis of different cell populations rather than reflecting intrinsic differences in radiosensitivity.     

Does On‐Pump/Beating‐Heart Coronary Artery Bypass Grafting Offer Better Outcome in End‐Stage Coronary Artery Disease Patients?

OBJECTIVES: The purpose of our study was to evaluate in a cohort of end-stage coronary artery disease (ESCAD) patients the effects of on-pump/beating-heart versus conventional coronary artery bypass grafting (CABG) requiring cardioplegic arrest. We report early and midterm survival, morbidity, and improvement of left ventricular (LV) function. METHODS: Between January 1992 and October 1999, 107 (Group I) ESCAD patients underwent on-pump/beating-heart surgery and 191 (Group II) ESCAD patients underwent conventional CABG requiring cardioplegic arrest. Mean age in Group I was 65.8 +/- 6.5 years (58-79 years); New York Heart Association (NYHA) and Canadian Cardiovascular Society (CCS) classifications were 3.2 +/- 0.4 and 3.3 +/- 0.5, respectively. LV ejection fraction (LVEF) was 24.8% +/- 4%, LV end diastolic pressure (LVEDP) was 28.2 +/- 3.8 mmHg, and LV end diastolic diameter (LVEDD) was 69.6 +/- 4.6 mm. Mean age in Group II was 64.1 +/- 5 years (57-76 years), NYHA class was 3 +/- 0.6, CCS class was 3.4 +/- 0.4, LVEF was 26.2% +/- 4.3%, LVEDP was 27.2 +/- 3.4 mmHg, and LVED was 68 +/- 4.2 mm. RESULTS: Preoperatively, Group I patients versus Group II patients had a markedly depressed LV function (LVEF, p = 0.006; LVEDP, p = 0.02; LVEDD, p = 0.003; and NYHA class, p = 0.002), older age (p = 0.012), and higher incidences of multiple acute myocardial infarction (AMI; p = 0.004), cardiovascular disease (CVD; p = 0.008), and chronic renal failure (CRH, p = 0.002). Cardiopulmonary bypass (CPB) time was longer in Group II patients (p = 0.028). The mean distal anastomosis per patient was similar between groups (p = NS). Operative mortality between Groups I and II was 7 (6.5%) and 19 (10%), respectively (p = NS). Perioperative AMI (p = 0.034), low cardiac output syndrome (LCOS; p = 0.011), necessity for ultrafiltration (p = 0.017), and bleeding (p = 0.012) were higher in Group II. Improvement of LV function within 3 months after the surgical procedure was markedly higher in Group I, demonstrated by increased LVEF (p = 0.035), lower LVEDP (p = 0.027), and LVEDD (p = 0.001) versus the preoperative data in Group II. The actuarial survivals at 1, 3, and 5 years were 95%, 86%, and 73% in Group I and 95%, 84%, and 72% in Group II (p = NS). CONCLUSIONS: ESCAD patients with bypassable vessels to two or more regions of reversible ischemia can undergo safe CABG with acceptable hospital survival and mortality and morbidity. In higher risk ESCAD patients, who may poorly tolerate cardioplegic arrest, on-pump/beating-heart CABG may be an acceptable alternative associated with lower postoperative mortality and morbidity. Such a technique offers better myocardial and renal protection associated with lower postoperative complications.